Alcohol consumption is common in HIV infected individuals and heavy alcohol consumption has been associated with accelerated HIV disease progression and poor health outcomes. This proposal will investigate mechanism underlying CD4 T cell decline and HIV disease progression in HIV infected women who engage in heavy alcohol consumption. One mechanism by which alcohol may cause immune dysfunction is by inducing microbial translocation. We will examine whether chronic cumulative exposure (amount x duration) over 10 years of observation period is associated with more rapid CD4 T cell decline and immune dysfunctionality namely exacerbation in levels of immune activation, inflammation and immune senescence leading to early advent of AIDS and Non AIDS co-morbidities. We will test our hypothesis that heavy alcohol consumption, defined using NIAAA criteria for hazardous drinking (for women, >7drinks/week or >3 drinks per occasion), disrupts the gut barrier causing microbial translocation which enhances systemic immune activation, inflammation and senescence;all events that contribute to CD4 T-cell decline and HIV disease progression. We will conduct this study retrospectively in bioreposited specimens from the longitudinal cohort, the Women's Interagency HIV Study. As a secondary aim linked to the other UO-1 in this consortium;a randomized clinical trial on alcohol reduction medication naltrexone, we will examine in subset of HIV infected heavy drinkers, whether alcohol reduction medication, naltrexone improves alcohol related immune dysregulation. We will create a repository and database of immune markers (translocation, immune activation, inflammation, and immune senescence) in HIV infected women who engage in hazardous drinking;which can be used for future translational studies related to alcohol and HIV interaction: observational or mechanistic. This project has a cross discipline expertise, from leading clinicians in the HIV/AIDS field, behavioral scientists, epidemiologist, and immunologist for successful implementation of the aims and objectives of this study. PUBLIC HEALTH RELEVANCE: Should microbial translocation prove to be the detrimental pathway due to chronic alcohol use, this research will give leads to developing new modalities to improve gut environment. The results of this study will lay emphasis on behavioral mechanisms such as alcohol use that could be a contributing to the unresolved problem of activation/inflammation and non AIDS defining co-morbidities despite effective HAART.